Illicit drug use continues to be a major public health concern in the United States. According to the US Department of Health and Human Services' 2009 National Survey on Drug Use and Health (US DDHS Report, 2009), an estimated 8.7% (21.8 million) of Americans age 12 or older reported being “current” illicit drug users, defined as having used a drug within one month of the survey. While the estimated number of American cocaine users age 12 or older has declined somewhat since 2006, it remains a major health concern, with approx. 16.7 million Americans (0.7% of the population) claiming to have used cocaine within a month of answering the survey. In addition, cocaine use is often seen as a complicating factor in cases of polyaddiction. There is a high prevalence of co-use of cocaine among heroin users (Leri et al., 2003). A high level of cocaine use has been shown to be an independent predictor of poor treatment outcome among heroin-dependent polydrug abusers (Downey et al., 2000). A degree of success in reducing heroin intake has been achieved through the use of opiate modulators such as methadone and buprenorphine (Stotts et al., 2009). However, studies suggest that the majority of cocaine/heroin abusers treated with methadone continued to use cocaine, even when the methadone reduced their heroin intake (Hartel et al., 1995; Magura et al., 1998). Thus, cocaine abuse represents a significant and complex health issue.
Addiction and recovery from addiction are characterized by a number of stages, each of which involves adaptations by various neurotransmitter systems (La Moel and Koob, 2007). In the early stages of the addiction process, the substance's ability to deliver reward plays a major role in drug use and continued use. As neuroadaptations take place over time, negative reinforcement augments the reward value of the drug, leading to dependence. Ultimately, when the drug is withdrawn after the establishment of dependence, a craving state occurs which can lead to relapse. Chronic exposure to cocaine induces marked alterations to the brain that make it difficult for many victims to withdraw from their use (Kreek and Koob, 1998; Bossert et al., 2005; Kreek et al., 2009). Dopaminergic signaling pathways play an important role in the reward learning and hedonic effects of cocaine abuse. However, several neurotransmitter systems may also be involved in addiction, including γ-aminobutyric acid (GABA), endocannabanoids, glutamate, endogenous opioids and serotonin (Goldstein and Volkow, 2002; Kalivas and Volkow, 2005). This complexity has made treatment of cocaine dependence a difficult goal to achieve. There are currently no FDA-approved medications for the treatment for cocaine addiction or withdrawal and there remains an urgent need for such medications (Van den Brink and van Ree, 2003; Kenna et al., 2007).
A number of marketed drugs and experimental agents targeting many of these neurotransmitter systems have recently entered clinical trials for the treatment of cocaine. Conventional efforts have targeted dopamine, serotonin, and norepinephrine systems. The strategy has resulted in the evaluation of at least 14 drugs as potential treatments (e.g. dopamine transporter inhibitors, L-DOPA, monoamine oxidase type B isozyme inhibitors, dopamine-releasing agents, dopamine D3 antagonists, 5-HT1A partial agonists, 5-HT reuptake inhibitors, etc.) (Vorel et al., 2002). Most of these agents produce adverse effects, including abuse liability, which limit their usefulness as abuse-deterrents. Other compounds being tested for cocaine addiction treatment are an anti-cocaine vaccine that retards entry of cocaine into the brain and a bacterial cocaine esterase that hydrolyzes cocaine into a nonpsychoactive metabolite (Ko et al., 2009; Kinsey et al., 2010). However, evidence that cocaine esterase has limited value in treating cocaine toxicity underscores the need to investigate alternative approaches (Shy et al., 2010).
Separately, Glioblastomas are malignant astrocytic tumors (WHO grade 4) and the most frequently occurring brain tumors. Disease prevalence is 1/100,000, and approximately 19,000 cases and 13,000 glioma related deaths are reported in the U.S. annually (Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C. and Thun, M. J. CA Cancer J. Clin. 2006, 56, 106-130.) Glioblastomas can occur at any age, but 70% of cases occur in patients between 45 and 70. In addition, malignant gliomas are the most common solid cancer in children (Maher, C. O. and Raffel C. Pediatr. Clin. North Am. 2004, 51, 327-357). Survival time can be up to 5 years, but patients with glioblastoma multiforme (GBM), a deadly, invasive tumor, succumb to the disease within 6-12 months (Huncharek, M. and Muscat, J. Anticancer Res. 1998, 18, 1303-1311). The disease progresses rapidly (2-3 months) and symptoms resulting from intracranial hypertension are non-specific (headaches, vomiting, behavioral changes, neurological deficits), making diagnosis difficult. While there has been progress in developing new chemotherapeutic agents for many classes of cancer, there has been little progress towards the development of chemotherapeutic agents for malignant gliomas. Treatment options are limited, and often begin with surgery and biopsy to confirm diagnosis, but complete resection is rarely feasible, as tumor cells often infiltrate healthy brain tissue. Radiotherapy and chemotherapy can be employed, but the benefits from adjuvant treatments are modest as indicated by the minimal improvement in clinical outcomes using growth factor receptor antagonist treatments (EGFR, \PDGFR), mTOR inhibitors, AKT inhibitors, and PKC inhibitors ((a) Adamson C, Kanu O O, Mehta A I, Di C, Lin N, Mattox A K, Bigner D. D. Expert Opin. Investig. Drugs 2009, 18:1061-1083. (b) Dresemann G. Ann Oncol 2005; 16:1702-1708, Reardon, D. A., Egorin, M. J., Quinn, J. A., J. Clin Oncol 2005, 23, 9359-9368). Unfortunately, tumor incidence has increased over the past 30 years (Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C. and Thun, M. J. CA Cancer J. Clin. 2006, 56, 106-130) and prognosis is poor in the majority of cases (Azizi S. A. and Miyamoto C. J. Neurovirol. 1998, 4, 204-216).
Separately, Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. This leads to diminished motor function, muscle wasting, and death in 3-5 years. The lifetime risk of developing ALS is 1 in 1,000, and there are approximately 35,000 patients in the US with ALS. The financial burden of ALS is significant with late stage ventilation treatment typically lasting up to 2 years at a cost of up to $400K per year. To date, Riluzole is the only medication approved for the treatment of ALS. The current standard of care is 50 mg of Riluzole daily and palliative drugs to address disease symptoms. The clinical efficacy of this therapy is limited, however, as it increases life expectancy by only 2-3 months after 15 months of treatment.
It has been demonstrated that nearly 75% of ALS patients have significantly decreased GLT-1 levels, which contributes to the rapid decline of patients via glutamate toxicity and neuronal cell death. Modulation of GLT-1 expression levels in ALS patients is an attractive target for therapeutic intervention in ALS. The SOD1 mouse model of ALS is based upon the decreased expression of GLT-1 in this strain of mouse. It has been demonstrated that ceftriaxone, a beta-lactam antibiotic, increases the expression of GLT-1 in the SOD1 mouse model of ALS, and this increase in GLT-1 increases the mean survival time of the SOD1 mouse through increased expression of GLT-1 (Rothstein, J. D.; Patel, S.; Regan, M. R.; Haenggeli, C.; Huang, Y. H.; Bergles, D. E.; Jin, L.; Hoberg, M. D.; Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijn, L. I.; Su, Z. Z.; Gupta, P; Fisher, P. B. Nature, 2005, 433, 73-77). Harmine, a beta-carboline alkaloid, also increases GLT-1 expression in the SOD1 mouse model of ALS (Li, Y.; Sattler, R.; Yang, E. J.; Nunes, A.; Ayukawa, Y.; Akhtar, S.; Ji, G.; Zhang, P. W; Rothstein, J. R. Neuropharmacology, 2011, 60, 1168-1175). Neither of these compounds has been approved for clinical uses as a treatment for ALS, and to date there are no modulators of glutamate uptake available for clinical use as treatments for ALS.